000154267 001__ 154267
000154267 005__ 20240529143839.0
000154267 0247_ $$2doi$$a10.1172/JCI136363
000154267 0247_ $$2pmid$$apmid:32780722
000154267 0247_ $$2pmc$$apmc:PMC7598066
000154267 0247_ $$2ISSN$$a0021-9738
000154267 0247_ $$2ISSN$$a1558-8238
000154267 0247_ $$2altmetric$$aaltmetric:88137884
000154267 037__ $$aDZNE-2021-00121
000154267 041__ $$aEnglish
000154267 082__ $$a610
000154267 1001_ $$aSchriever, Sonja C$$b0
000154267 245__ $$aType 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity.
000154267 260__ $$aAnn Arbor, Mich.$$bASCJ$$c2020
000154267 3367_ $$2DRIVER$$aarticle
000154267 3367_ $$2DataCite$$aOutput Types/Journal article
000154267 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1712756148_11350
000154267 3367_ $$2BibTeX$$aARTICLE
000154267 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000154267 3367_ $$00$$2EndNote$$aJournal Article
000154267 500__ $$aISSN 1558-8238 not unique: **3 hits**.
000154267 520__ $$aRecent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D.
000154267 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000154267 588__ $$aDataset connected to CrossRef, PubMed, , Journals: pub.dzne.de
000154267 650_7 $$2Other$$aDiabetes
000154267 650_7 $$2Other$$aMetabolism
000154267 650_7 $$2Other$$aObesity
000154267 650_7 $$0EC 2.7.12.2$$2NLM Chemicals$$aMAP Kinase Kinase 4
000154267 650_7 $$0EC 3.1.3.16$$2NLM Chemicals$$aDUSP8 protein, mouse
000154267 650_7 $$0EC 3.1.3.48$$2NLM Chemicals$$aDual-Specificity Phosphatases
000154267 650_2 $$2MeSH$$aAnimals
000154267 650_2 $$2MeSH$$aDiabetes Mellitus, Experimental: enzymology
000154267 650_2 $$2MeSH$$aDiabetes Mellitus, Experimental: genetics
000154267 650_2 $$2MeSH$$aDiabetes Mellitus, Type 2: enzymology
000154267 650_2 $$2MeSH$$aDiabetes Mellitus, Type 2: genetics
000154267 650_2 $$2MeSH$$aDual-Specificity Phosphatases: genetics
000154267 650_2 $$2MeSH$$aDual-Specificity Phosphatases: metabolism
000154267 650_2 $$2MeSH$$aHypothalamus: enzymology
000154267 650_2 $$2MeSH$$aInsulin Resistance
000154267 650_2 $$2MeSH$$aMAP Kinase Kinase 4: genetics
000154267 650_2 $$2MeSH$$aMAP Kinase Kinase 4: metabolism
000154267 650_2 $$2MeSH$$aMice
000154267 650_2 $$2MeSH$$aMice, Knockout
000154267 650_2 $$2MeSH$$aSignal Transduction
000154267 7001_ $$aKabra, Dhiraj G$$b1
000154267 7001_ $$aPfuhlmann, Katrin$$b2
000154267 7001_ $$aBaumann, Peter$$b3
000154267 7001_ $$aBaumgart, Emily V$$b4
000154267 7001_ $$aNagler, Joachim$$b5
000154267 7001_ $$aSeebacher, Fabian$$b6
000154267 7001_ $$aHarrison, Luke$$b7
000154267 7001_ $$aIrmler, Martin$$b8
000154267 7001_ $$aKullmann, Stephanie$$b9
000154267 7001_ $$aCorrêa-da-Silva, Felipe$$b10
000154267 7001_ $$0P:(DE-HGF)0$$aGiesert, Florian$$b11
000154267 7001_ $$aJain, Ruchi$$b12
000154267 7001_ $$aSchug, Hannah$$b13
000154267 7001_ $$aCastel, Julien$$b14
000154267 7001_ $$aMartinez, Sarah$$b15
000154267 7001_ $$aWu, Moya$$b16
000154267 7001_ $$aHäring, Hans-Ulrich$$b17
000154267 7001_ $$0P:(DE-HGF)0$$ade Angelis, Martin Hrabe$$b18
000154267 7001_ $$aBeckers, Johannes$$b19
000154267 7001_ $$aMüller, Timo D$$b20
000154267 7001_ $$aStemmer, Kerstin$$b21
000154267 7001_ $$0P:(DE-2719)2000028$$aWurst, Wolfgang$$b22$$udzne
000154267 7001_ $$aRozman, Jan$$b23
000154267 7001_ $$aNogueiras, Ruben$$b24
000154267 7001_ $$aDe Angelis, Meri$$b25
000154267 7001_ $$aMolkentin, Jeffery D$$b26
000154267 7001_ $$aKrahmer, Natalie$$b27
000154267 7001_ $$aYi, Chun-Xia$$b28
000154267 7001_ $$aSchmidt, Mathias V$$b29
000154267 7001_ $$aLuquet, Serge$$b30
000154267 7001_ $$aHeni, Martin$$b31
000154267 7001_ $$aTschöp, Matthias H$$b32
000154267 7001_ $$aPfluger, Paul T$$b33
000154267 773__ $$0PERI:(DE-600)2018375-6$$a10.1172/JCI136363$$gVol. 130, no. 11, p. 6093 - 6108$$n11$$p6093 - 6108$$tThe journal of clinical investigation$$v130$$x1558-8238$$y2020
000154267 8564_ $$uhttps://www.jci.org/articles/view/136363
000154267 8564_ $$uhttps://pub.dzne.de/record/154267/files/DZNE-2021-00121_Restricted.pdf
000154267 8564_ $$uhttps://pub.dzne.de/record/154267/files/DZNE-2021-00121_Restricted.pdf?subformat=pdfa$$xpdfa
000154267 909CO $$ooai:pub.dzne.de:154267$$pVDB
000154267 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2000028$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b22$$kDZNE
000154267 9131_ $$0G:(DE-HGF)POF3-342$$1G:(DE-HGF)POF3-340$$2G:(DE-HGF)POF3-300$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lErkrankungen des Nervensystems$$vDisease Mechanisms and Model Systems$$x0
000154267 9132_ $$0G:(DE-HGF)POF4-899$$1G:(DE-HGF)POF4-890$$2G:(DE-HGF)POF4-800$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bProgrammungebundene Forschung$$lohne Programm$$vohne Topic$$x0
000154267 9141_ $$y2020
000154267 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2021-01-27
000154267 915__ $$0StatID:(DE-HGF)1190$$2StatID$$aDBCoverage$$bBiological Abstracts$$d2021-01-27
000154267 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2021-01-27
000154267 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bJ CLIN INVEST : 2021$$d2022-11-30
000154267 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2022-11-30
000154267 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2022-11-30
000154267 915__ $$0StatID:(DE-HGF)0501$$2StatID$$aDBCoverage$$bDOAJ Seal$$d2022-08-11T09:34:18Z
000154267 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bDOAJ : Peer review$$d2022-08-11T09:34:18Z
000154267 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search$$d2022-11-30
000154267 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC$$d2022-11-30
000154267 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2022-11-30
000154267 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2022-11-30
000154267 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2022-11-30
000154267 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences$$d2022-11-30
000154267 915__ $$0StatID:(DE-HGF)9915$$2StatID$$aIF >= 15$$bJ CLIN INVEST : 2021$$d2022-11-30
000154267 9201_ $$0I:(DE-2719)6000016$$kMünchen common$$lMünchen common$$x0
000154267 9201_ $$0I:(DE-2719)1140001$$kAG Wurst$$lGenome Engineering$$x1
000154267 980__ $$ajournal
000154267 980__ $$aVDB
000154267 980__ $$aI:(DE-2719)6000016
000154267 980__ $$aI:(DE-2719)1140001
000154267 980__ $$aUNRESTRICTED